Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis

Zhengbo Song,Xuefeng Xia,Ling Yang,Guoping Cheng,Xin Yi,Pansong Li,Lianpeng Chang,Yanfang Guan,Ming Chen,Yiping Zhang,Wenxian Wang,Rongrong Chen,Rongrong Zhou,Zhipeng Zhou

doi:10.1038/s41419-021-03410-7

Abstract

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

Highlights

IntroductionBrain metastases (BM) are detected at non-small-cell lung cancer (NSCLC) patients with early stage primary tumor receiving surgical resection are found to exhibit recurrence in the form of BM2
Lung cancer is the most common cause of cancer death worldwide
Clinical characteristics of patients Thirty-three patients with lung carcinoma were enrolled in this study, with median age of 58-year old and with more male patients (73%) than female patients (27%)

Summary

Introduction

Brain metastases (BM) are detected at NSCLC patients with early stage primary tumor receiving surgical resection are found to exhibit recurrence in the form of BM2. Song et al Cell Death and Disease (2021)12:106. Bevacizumab added to various chemotherapy agents or erlotinib in patients with NSCLC for BM showed safety and low incidence of CNS hemorrhage[9]. Immunotherapy with PD-1 or PD-L1 inhibitors is generally accepted treatment option for patients with advanced lung cancer, whether as a single agent or in combination with chemotherapy[10,11]. In the first-line KEYNOTE-189 trial[10] and the second-line OAK trial[12], patients with immunotherapy-treated BM in subgroup showed a longer overall survival (OS) than chemotherapy-treated. A recent phase 2 trial reported that pembrolizumab had activity in BM from NSCLC with PD-L1 expression at least 1% and was safe in selected patients with untreated BM13

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Results

Conclusion